# Cell model for KSHV infection and genetic manipulation

> **NIH NIH R01** · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · 2024 · $569,871

## Abstract

Cancer cells depend on reprogrammed metabolic pathways for anabolic proliferation. Discovering these cancer
metabolic vulnerabilities can reveal novel targets for therapy. Kaposi’s sarcoma-associated herpesvirus (KSHV)
is the causal agent of Kaposi’s sarcoma (KS) and several other cancers. Despite intensive studies for several
decades, there is currently no effective therapy for KS. Our long-term goal is to delineate the pathogenesis of
KSHV-induced cancers, providing a scientific basis for developing novel therapies. Toward this goal, we have
previously developed an efficient system of KSHV-induced cellular transformation of primary cells and a reverse
genetics system for KSHV mutagenesis. Using these powerful systems, in the current funding period, we have
delineated viral and cellular genes that are essential for KSHV-induced cellular transformation and identified
novel therapeutic targets and agents that have the potentials for translating into clinics. In particular, we have
recently discovered that KSHV-transformed cells are addicted to glutamine. Unlike other types of cancer cells
that utilize glutamine to replenish the TCA cycle, glutamine is primarily shunted to nucleotides syntheses by
providing the critical g-nitrogen in addition to amino acids. KSHV hijacks numerous rate-limiting enzymes in these
pathways, including phosphoribosyl pyrophosphate amidotransferase (PPAT) and phosphoribosyl
pyrophosphate synthetases 1 (PRPS1), which is upregulated in KS spindle tumor cells. Significantly, knockdown
of these enzymes suppresses the proliferation of KSHV-transformed cells but has no effect on the
primary/uninfected cells. Our hypothesis is that KSHV encodes specific gene(s) to hijack the nucleotide
synthesis pathways to support the proliferation and survival of KSHV-transformed cells, and hence
targeting these pathways is effective for therapy of KSHV-induced tumors. We have developed 3D Culture
systems that closely representing in vivo metabolic changes, an innovative nanoparticles carbon-dots (Cdots)-
mediated delivery approach for locked nucleic acid (LNA)-siRNAs, and cutting-edge technology of metabolomics
for tracing the carbon and nitrogen flows. We will determine the essential roles of the dysregulated nucleotide
synthesis pathways for KSHV-induced cellular transformation and tumorigenesis (Aim 1); determine the
mechanisms by which KSHV hijacks the nucleotide synthesis pathways for supporting the proliferation and
survival of KSHV-transformed cells (Aim 2); and target vulnerable genes in the nucleotide pathways using the
Cdots-mediated delivery approach for treating KSHV-induced tumorigenesis (Aim 3). The proposed project is
highly significant as it will test a novel hypothesis of KSHV manipulation of key cellular metabolic pathways
using multidisciplinary innovative approaches and model systems. It is our expectation that the
accomplishment of this project will lead to the identification of novel cancer vulnerabilities of KSHV-induce...

## Key facts

- **NIH application ID:** 10883700
- **Project number:** 5R01CA096512-17
- **Recipient organization:** UNIVERSITY OF PITTSBURGH AT PITTSBURGH
- **Principal Investigator:** Shou-Jiang Gao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $569,871
- **Award type:** 5
- **Project period:** 2003-01-13 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10883700

## Citation

> US National Institutes of Health, RePORTER application 10883700, Cell model for KSHV infection and genetic manipulation (5R01CA096512-17). Retrieved via AI Analytics 2026-06-30 from https://api.ai-analytics.org/grant/nih/10883700. Licensed CC0.

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